New insights to the brain functions of prolyl oligopeptidase

University of Helsinki, Faculty of Pharmacy, Farmakologian ja toksikologian osasto

en

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Peltonen, Iida

fi

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2012-09-26T09:30:55Z

dc.date.available

2012-10-23

fi

dc.date.available

2012-09-26T09:30:55Z

dc.date.issued

2012-11-02

fi

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URN:ISBN:978-952-10-8289-4

fi

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http://hdl.handle.net/10138/36921

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Prolyl oligopeptidase (PREP, also known as POP; EC 3.4.21.26) is an 80-kDa serine protease hydrolyzing peptides smaller than 30-mer at the carboxyl side of an internal proline-residue. PREP is widely distributed in the body and the cytosolic form is abundantly expressed also in the brain. Several neuropeptides have been suggested to be hydrolyzed by PREP, such as arginine-vasopressin (AVP), oxytocin and substance P (SP), through which PREP has been connected to central nervous system (CNS) functions including learning, memory and mood. However, the break-down of these peptides by PREP has not been conclusively demonstrated in vivo. One of the major criticisms against the neuropeptide theory has been the different locations of intracellular PREP and the mainly extracellular neuropeptides. Although PREP has mostly been studied as a neuropeptide-cleaving enzyme, there are also other connections between PREP and brain diseases, such as the altered levels of PREP in the plasma of patients with CNS disorders and the location of PREP in neurons connected to important brain functions. Recent studies show that PREP may have effects on intracellular protein aggregation via protein-protein interactions.
The purpose of this study was to find novel actions and elucidate the relevance of proposed physiological roles of PREP in the rodent brain using different neurochemical and behavioural methods. Brain penetrating PREP inhibitors were used as tools in many of the studies. First, we studied the PREP inhibition capabilities of common psychoactive drugs. Since the pathophysiology of CNS diseases is not fully understood, we tested whether PREP could be a physiological target for these compounds. Second, we examined the colocalization and interaction of PREP with several neurotransmitter systems by lesioning the major nuclei of these transmitters with neurotoxins and then studying the effects of the lesions on PREP activity and immunoreactivity in the respective projection areas. Third, the colocalization and functional interaction of PREP with neurotensin and its receptor NTS1 were studied in the midbrain dopaminergic pathways. Finally, the effect of PREP inhibition on behaviour was tested in animal models of memory, locomotor activity and Parkinson s disease.
We found that psychoactive compounds did not considerably inhibit PREP at concentrations achieved in the human therapy. Lesioning of the major neurotransmitter nuclei did not affect PREP activity or immunoreactivity in the projection areas indicating that PREP is not present in the long projection neurons or not connected to their functions. PREP was highly colocalized with neurotensin and NTS1 in the ventral tegmental area (VTA) and with NTS1 in the substantia nigra (SN). In addition, PREP inhibitor was shown to increase the dopamine levels in the SN and VTA in a NTS1-dependent manner. We found also that PREP inhibition increases locomotor activity in rats, but does not improve memory or affect rotational behaviour in a rat model of Parkinson s disease.
Conclusively, although the precise role of PREP in the brain remains unclear, our studies substantiated the view that the major physiological role for PREP in the brain is not the improvement of memory. Interestingly, our results suggested that PREP may be involved in motor functions and in the neurotensin-mediated dopaminergic signalling in the SN and VTA through intracellular mechanisms.